Unravelling Congestion in Heart Failure: Mechanisms, Diagnosis and Treatment

Abstract

Heart failure exerts a significant and growing burden on public health globally. It currently afflicts approximately 2% of the adult Western population, impacting the lives of an estimated 64.3 million individuals across the world 1. This alarming prevalence is further underscored by the fact that heart failure ranks as the primary cause for hospital admissions, accounting for 1-2% of all admissions and representing the most prevalent reason for hospitalization among the elderly 1. Despite a modest decline in the overall incidence of heart failure in Europe, its prevalence continues to surge due to the improved treatment options, which has substantially prolonged the life expectancy of patients with heart failure 2. This perpetuates the significance of heart failure as a pressing public health concern. Heart failure is a multifaceted syndrome characterized by diverse causes, disease trajectories, and phenotypes. At its core, heart failure manifests when the heart cannot supply sufficient cardiac output to meet the body's metabolic demands. Various cardiac and non-cardiac conditions, including cardiomyopathy, coronary artery disease, valvular heart disease, arrhythmias, and pericardial disease, can either present as heart failure or progress to it when left untreated. While multiple diagnostic criteria and classifications have been proposed 3–5, a recent universal definition introduced by an expert panel aims to streamline and standardize heart failure diagnosis and classification globally 6: Congestion plays a pivotal role in this universal definition, representing one of the hallmark signs of heart failure. It is the downstream effect of neurohormonal activation that occurs in response to an insufficient cardiac output. Lower intraaortic pressures lead to increased sympathetic activation, which in turn decreases renal perfusion and directly stimulates renin release 7. Simultaneously, heart failure directly impacts renal perfusion, further stimulating renin secretion and intensifying the renin-angiotensin-aldosterone system.7. This neurohormonal activation results in renal sodium and water retention, expanding both intravascular and extravascular volumes and culminating in congestion. Beyond its diagnostic relevance, congestion significantly impacts patients' quality of life 8 and stands as the primary reason for hospitalization among heart failure patients 9. Furthermore, congestion can impair target organ function, which is associated with increased mortality 10. Despite its ubiquitous presence in heart failure, the methods for diagnosing, monitoring, and treating congestion have seen limited advancements in recent decades. Physicians still often rely solely on clinical examinations to detect and monitor congestion. However, the most common clinical signs lack sufficient sensitivity and specificity11. Echocardiography can definitely aid in early detection of congestion, but it is technically challenging and not readily available. Furthermore, serial assessment with echocardiography to monitor congestion remains impractical on a large scale. Thus, alternative methods are imperative for the timely detection and monitoring of congestion, enabling early intervention to prevent patient deterioration and hospitalization. Recently, the use of ultrasound to detect organ congestion, such as lung ultrasound for detecting and monitoring lung congestion, has gained interest 12. These relatively simple techniques might improve the monitoring of congestion and help to guide decongestive therapies. However, these ultrasound techniques require further investigation before large scale implementation can be suggested. Additionally, the implantation of sensors in the pulmonary artery tree allows for wireless monitoring of pulmonary artery pressures as an indicator of congestion 13. Trial data support its use, but real-world data, especially from Europe are needed to further define their role in heart failure care. The most important advances in the treatment of congestion have been the introduction of neurohormonal blockers at the end of the previous century14–16. These agents prevent congestion upstream and reduce heart failure hospitalizations and mortality in patients with heart failure and reduced ejection fraction. In the last years, therapy was further improved with the use of angiotensin receptor – neprilysin inhibitors (ARNI) 17 and sodium-glucose cotransporter-2 inhibitors (SGLT2i) 18,19. However, there has been a relative lack of breakthroughs in the specific treatment of congestion. Furthermore, for patients with heart failure with preserved ejection fraction, SGLT2i are currently the only agents that reduce the risk of heart failure hospitalization 20,21. Loop diuretics remain the cornerstone treatment for congestion, yet their use relies primarily on clinical experience and expert opinion. 22. Moreover, a significant knowledge gap existed regarding the use of diuretics until recently. Several trials, including the Cardiorenal Rescue Study in Acute Decompensated Heart Failure (CARRESS-HF) 23, Diuretic Optimization Strategies Evaluation (DOSE) 24, and Aldosterone Targeted Neurohormonal Combined with Natriuresis Therapy in Heart Failure (ATHENA) 25 trials, have explored diuretic strategies in acute heart failure. However, none of these trials has provided conclusive evidence for an optimal diuretic approach. Consequently, many patients are discharged while still experiencing congestion, which has been associated with worse prognosis 26–28 , emphasizing the urgent need to enhance decongestion strategies. Loop diuretics are also commonly used in ambulatory heart failure patients to prevent or treat congestion. However, their use has not consistently improved outcomes 29. The decision to continue loop diuretics as maintenance therapy likely depends on the control of the underlying heart failure. Determining which patients can safely discontinue loop diuretics remains a challenge, as current data are insufficient to guide selection criteria. Similarly, sodium restriction is advised for most heart failure patients to prevent congestion 3,4, but recent studies have failed to demonstrate significant benefits on outcomes 30. With neurohormonal blockers reducing renal sodium avidity and congestion episodes, the role of routine sodium restriction in heart failure management is unclear. Apparently, selected patients with heart failure with reduced ejection fraction can tolerate high sodium intake (up to 4.7 g per day) 31, but the mechanisms behind this remain unelucidated. A specific population of interest is patients with post-myocardial infarction left ventricular dysfunction. Despite the proven benefits of neurohormonal blockers, recent trials such as the Prospective ARNI vs. ACE inhibitor trial to Determine Superiority in reducing heart failure Events after Myocardial Infarction (PARADISE-MI) have shown no advantage of ARNI over angiotensin-converting enzyme inhibitors in these patients 32. This may be attributed to changes in myocardial infarction treatment practices over the years, with early reperfusion and left ventricular function recovery 33. However, most data on left ventricular dysfunction predate these advancements, necessitating updated information to better understand the development of heart failure and congestion in the current era. The trajectory of heart failure and congestion prevention is not solely dependent on pharmacological approaches; cardiac implantable electronic devices, particularly cardiac resynchronization therapy, play a pivotal role. However, there remains underutilization of these devices, primarily due to inadequate referrals from primary and secondary care providers 34. Enhancing our understanding of device functionality and patient selection criteria could facilitate better implementation. This doctoral thesis aims to address the aforementioned challenges. It seeks to provide insights into congestion pathophysiology, detection, monitoring, and optimization of treatment strategies. Additionally, it will focus on post-infarction left ventricular dysfunction, providing much-needed contemporary data. Finally, the thesis will explore ways to enhance the utilization of cardiac implantable electronic devices in heart failure management. By delving into these critical areas, this thesis endeavors to contribute to the advancement of heart failure management and the improvement of patient outcomes.